Animals that were given daily feed containing 0.1% metformin had an average 5.83% increase in lifespan compared with control mice that didn't get the drug (P=0.02), Rafael de Cabo, PhD, of the National Institute on Aging in Baltimore, and colleagues reported online in Nature Communications.

But the lifespan of mice given feed that contained 1% metformin was significantly shortened by 14.4%, indicating a sweet spot for chronic, beneficial doses of the drug.

Filipe Cabreiro, PhD, of University College London, who was not involved in this study but who has studied the effects of metformin on the lifespan of the nematode C. elegans, told MedPage Today that the dose-dependent effects were an "interesting observation."

"This study clearly illustrates the importance of designing new studies to unravel the molecular targets of metformin and maximize its potential and therapeutic applications," Cabreiro said in an email.

Researchers have been interested in metformin's anti-aging effects because the drug has proven to be good at diminishing conditions that have a strong age-related component, including cardiovascular disease and cancer. They've argued that the drug appears to mimic the effects of calorie restriction and could hold similar anti-aging benefits as seen with such diets.

Indeed, in their research, Cabreiro and colleagues found that metformin extended the lifespan of C. elegans, but there have been conflicting results about its benefits in drosophila and other animal studies.

In the current study, de Cabo and colleagues looked at the effects in mice -- particularly, middle-aged male mice that were randomized to one of three diets: a standard diet, one that was supplemented with 0.1% metformin every day, or one that was supplemented with daily 1% metformin.

They found that male mice on the 0.1% metformin treatment had an increase in lifespan compared with control mice that didn't get metformin (P=0.02). The researchers also saw similar life-extending results in a different strain of mice, confirming that the "effects of metformin in longevity are not strain-specific."

But the 1% metformin treatment had the opposite effect -- it shortened the lifespan of the mice compared with the control group.

The difference was likely due to kidney failure, the researchers said, adding that high doses of metformin have been associated with the development of lactic acidosis, and the drug is contraindicated in patients with kidney dysfunction.

The lower metformin dose didn't appear to have any negative effects on the kidneys, and had other beneficial effects on metabolism. Mice on the 0.1% dose weighed less than control group mice despite consuming more calories, an indication that metformin increased their use of fat for energy.

This group also tended to preserve body weight as they got older, which has been associated with increased survival in rodent and human studies, the researchers said.

Metformin also prevented the onset of metabolic syndrome. At 100 weeks old, metformin-treated mice had improvements in metabolic parameters, including reductions in insulin, total cholesterol, LDL cholesterol, and Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR), the researchers found.

In genome-wide microarray analysis of liver and muscle tissues, mice on low-dose metformin also had a global gene expression profile that resembled one seen with calorie restriction. De Cabo and colleagues saw significant overlap in the number of upregulated and downregulated gene sets in liver (84.7%) and muscle (85.6%) tissue, supporting the idea that metformin "closely mimics the calorie-restriction transcriptome," they wrote.

And in an analysis of mouse livers, metformin increased the levels of phospohoactive adenosine monophosphate-activated protein kinase (AMPK) -- an enzyme involved in energy balance and fat and glucose metabolism -- by 27% (P<0.05).

The researchers also observed a reduction in antioxidant activity and in chronic inflammation.

De Cabo and colleagues concluded that their findings justify further studies to determine if there's an exposure level of chronic metformin that could improve the health and lifespan of humans.

Farmhispania SA provided the metformin used in the study.

The research was supported in part by the National Institute on Aging and part of the work was done under a CRADA with SIRTRIS, a GlaxoSmithKline company.

The researchers reported no conflicts of interest.

Reviewed by F. Perry Wilson, MD, MSCE Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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